Solid lipid nanoparticles (SLN) constitute an alternative to other particulate systems for the delivery of active ingredients, such as emulsions, liposomes, micelles, microparticles and/or polymeric nanoparticles. SLN are generated by substituting the liquid lipid in the emulsions for a solid lipid, which means that the SLN are solid at room temperature as well as at body temperature.
The use of SLN as delivery systems enables the use of physiologically acceptable lipids, the possibility of avoiding the use of organic solvents in their preparation, and a wide range of routes of administration, which includes through the skin, orally or intravenously. As well as showing good bioavailability, their principal advantages are:
1. Protection of the active ingredient from chemical degradation. The lipid matrix of SLN can protect labile active ingredients from hydrolysis and/or oxidation, such as tocopherol, retinol and coenzyme Q10 [Gohla, S. et al. J. MicroencapsuL 18: 149-158 (2001); Schäfer-Korting, M. et al. Adv. Drug Del. Rev. 59: 427-443 (2007)].
2. Based on the composition of the lipid particles, they offer control of the speed of active ingredient release and therefore the possibility of achieving sustained release profiles [Mehnert, W. et al. Eur. J. Pharm. Biopharm. 45: 149-155 (1998)].
3. Control of dehydration of the skin due to an occlusive effect [Müller, R. H. et al. J. Cosm. Sci. 52: 313-323 (2001)].
4. According to its components they can act as ultraviolet radiation filters [Müller, R. H. et al. Int. J. Cosm. Sci. 23: 233-243 (2001)].
A new generation of solid lipid nanoparticles are the nanostructured lipid carriers (NLC). These systems have the same advantages as the SLN, and also minimize or avoid some possible problems associated with SLN, such as the low loading capacity and active ingredient expulsion during storage. In contrast to the at least partially crystalline state of the lipid phase in SLN, NLC show a less organized solid lipid matrix. In the case of NLC, there are both solid and liquid compounds in the matrix, thus the greater disorganization leads to the existence of a greater number of holes with the subsequent increase in the ability to encapsulate active ingredients. For the preparation of NLC, sterically very different molecules of lipids are mixed together, mixtures of solid lipids with liquid lipids or oils [Müller, R. H. et al. Adv. Drug Deliv. Rev. 54 (Suppl. 1): S131-S155 (2002)].
The SLN and NLC are from 50 nm to 1000 nm in size and are kept stabilized in an aqueous suspension by surfactants or hydrophilic polymers. The NLC and SLN are very suitable vehicles for releasing active ingredients through the skin. Better epidermal penetration of active ingredients is achieved when they are incorporated into SLN or NLC than when they are applied to the skin in the form of a solution or an emulsion.
The SLN have a solid lipid nucleus which can dissolve lipophilic drugs, which is the more common case for use. However, the possibility of incorporating peptides in lipid particles could constitute a protection of the active ingredient from the proteolytic degradation in the gastrointestinal apparatus. However, there are few references of the use of lipids as matrix materials for formulations of peptides and proteins, due to the hydrophobic nature of the lipid matrix, which makes it more appropriate for incorporating lipophilic active ingredients than hydrophilic proteins. The use of emulsions to incorporate hydrophilic active ingredients such as insulin in SLN is described [Gallarate, M. et al. J. Microencapsul. 26: 394-402 (2009)]. In the publication of Gallarate et al. the preparation method of SLN implies the use of organic solvents, a factor which is problematic due to the possible retention of their residues. Gasco et al. incorporate thymopentin pentapeptide in solid lipid nanoparticles by two different methods: the formation of a lipophilic ion-pair with hexadecylphosphate, or by the formation of a multiple emulsion w/o/w dissolving the peptide in the internal aqueous phase [Gasco, M. R. et al. Int. J. Pharm. 132: 259-261 (1996)]; this latter method is also used by the same authors to incorporate a polypeptide derived from LHRH in SLN [Gasco, M. R. et al. Int. J. Pharm. 105: R1-R3 (1994)]. Zhou et al. describe an increase in the efficiency of encapsulation and the load capacity in the incorporation into SLN of different proteins using PLGA (lactic and glycolic acid copolymer) as an emulsifier [Zhou, W. et al. Colloids and Surfaces, B: Biointerfaces, 67: 199-204 (2008)].
The encapsulation of hydrophilic compounds in SLN or NLC presents another problem, as would be the diffusion of the active ingredient within the system towards a medium where it would be more soluble, i.e., towards the aqueous system in which the lipid nanoparticles are in suspension.
Although the SLN and the NLC enable the chemical stability of the incorporated active ingredients to be improved, this stabilization is not complete. Surprisingly, the authors of this invention have found greater stabilization against degradation of cosmetic and/or pharmaceutical active ingredients incorporated into SLN or NLC when the SLN or NLC are polymerically coated [Spanish patent application ES P2010-30431].
The preparation procedures of the SLN and NLC, as well as the delivery system described by the authors in the Spanish patent application ES P2010-30431, implies the exposure of the active ingredient to be encapsulated to the temperatures of the melting points of the lipids in the matrix, which can be very high: over 50° C., and in most cases it is usual to heat the mixtures to about 80-90° C. In case of thermolabile active ingredients, like many biological compounds and others of synthetic origin such as synthetic peptides, this hinders the use of delivery systems based on solid lipids. The hydrophilic compounds can be incorporated into the lipid delivery system in the form of a stable microemulsion, which as well as stabilizing the active ingredient, promotes its bioavailability.
A microemulsion is defined as a system of water, oil and an amphiphile which is an optically isotropic and thermodynamically stable solution. Microemulsions are formed spontaneously. Ordinary emulsions, however, require energy for their formation and are thermodynamically unstable [Eastoe, J. Microemulsions, in “Colloid Science: principles, methods and applications”, Chapter 5. Ed. T. Cosgrove, John Wiley & Sons, Ltd (2005)].